Smoking related deaths in the US number over 440,000 per year and yet there are 46.2 million smokers in US alone (CDC, 2004). Nicotine is believed to be the primary addictive component of cigarettes, and thus it is critical to gain a better understanding of the mechanisms of nicotine reward and reinforcement. Repeated nicotine administration in animals leads to behavioral changes, such as locomotor sensitization and conditioned place preference, which are thought to reflect its reinforcing properties. In addition, nicotine administration modulates neuronal activity, neurotransmitter release and downstream signaling in the mesolimbic dopamine system, specifically in the ventral tegmental area (VTA) and nucleus accumbens. The calcium-dependent protein phosphatase, calcineurin, also modulates many of the signaling processes implicated in nicotine addiction. Thus, it is important to understand the role of calcineurin in nicotine- mediated behavioral and neurochemical plasticity. The proposed experiments will 1) determine the contribution of calcineurin activity in the VTA to chronic nicotine-induced locomotor sensitization and 2) characterize the role of VTA calcineurin in nicotine-mediated signaling pathways. [unreadable] [unreadable] [unreadable]